An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells |
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Authors: | Andrew Hale Changjin Lee Sofia Annis Pil-Ki Min Reena Pande Mark A Creager Colleen G Julian Lorna G Moore S Alex Mitsialis Sarah J Hwang Stella Kourembanas Stephen Y Chan |
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Institution: | 1. Division of Cardiovascular Medicine, Brigham and Women''s Hospital, Boston, MA 02115, USA;2. Division of Newborn Medicine, Boston Children''s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA;3. Cardiology Division, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea;4. Department of Emergency Medicine, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA;5. Department of Medicine, and Obstetrics-Gynecology, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA;6. Division of Network Medicine, Department of Medicine, Brigham and Women''s Hospital, Boston, MA, 02115, USA |
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Abstract: | Complex organisms may coordinate molecular responses to hypoxia by specialized avenues of communication across multiple tissues, but these mechanisms are poorly understood. Plasma-based, extracellular microRNAs have been described, yet their regulation and biological functions in hypoxia remain enigmatic. We found a unique pattern of release of the hypoxia-inducible microRNA-210 (miR-210) from hypoxic and reoxygenated cells. This microRNA is also elevated in human plasma in physiologic and pathologic conditions of altered oxygen demand and delivery. Released miR-210 can be delivered to recipient cells, and the suppression of its direct target ISCU and mitochondrial metabolism is primarily evident in hypoxia. To regulate these hypoxia-specific actions, prolyl-hydroxylation of Argonaute 2 acts as a molecular switch that reciprocally modulates miR-210 release and intracellular activity in source cells as well as regulates intracellular activity in recipient cells after miR-210 delivery. Therefore, Argonaute 2-dependent control of released miR-210 represents a unique communication system that integrates the hypoxic response across anatomically distinct cells, preventing unnecessary activity of delivered miR-210 in normoxia while still preparing recipient tissues for incipient hypoxic stress and accelerating adaptation. |
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Keywords: | Endothelial Circulating microRNA Hypoxia Hypoxamir Mitochondrial metabolism |
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